Long QT syndrome (LQTS) is associated with delayed cardiac repolarization, prolonged QT intervals, recurrent syncope, ventricular arrhythmias, and sudden death. Since mouse models for both LQT1 and LQT2 have failed to mimic the arrhythmias in human LQT1 and LQT2, we propose to create transgenic rabbit models deficient in /Ks and /Kr. In Specific Aim I we propose to generate transgenic rabbits overexpressing pore mutant of KvLQT1 in the heart in order to attenuate /Ks, as well as additional transgenic rabbits overexpressing pore mutant of HERG in the heart in order to attenuate /Kr. We next propose to analyze and compare the phenotype of these models with surface ECG, to monitor alert, free-moving rabbits, and to conduct programmed electrical stimulation (PES) of the right ventricle of anesthetized rabbits. In Specific Aim II, we propose to characterize the biochemical and electrophysiological phenotype of rabbit cardiomyocytes derived from the epicardial, mid-myocardial, and endocardial layers of the left ventricle of KvLQT1-DN and ERG-DN rabbits-specifically, to characterize and compare the expression of native potassium channel polypeptides, the action potential durations (APDs), the inward and outward potassium currents, and the inward calcium currents expressed in these cardiomyocytes. We will evaluate the effect of the adrenergic agonist isoproterenol on APDs and these inward and outward currents and correlate these findings with the functional studies described under Specific Aim III. In Specific Aim III, we propose to evaluate the effect of the beta adrenergic agonist isoproterenol on transmural distribution of transmembrane action potential characteristics across the ventricular wall in KvLQT1-DN and ERG-DN rabbit models using a wedge preparation. We will assess the contribution of transmural electrical heterogeneity induced by isoproterenol to the development of long QT intervals, broad-based T waves, transmural dispersion of repolarization, and the development of spontaneous and programmed electrical stimulation (PES)-induced TdP in the two models. Studies in these rabbits will likely provide new insights into the mechanisms that underlie the ventricular arrhythmias and the electrical remodeling occurring in LQT1 and LQT2. These models may also enable drug screening for acquired LQTS and the development of gene therapy for congenital LQTS.